scholarly journals Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Haya Al-Sulaiti ◽  
Ilhame Diboun ◽  
Maha V. Agha ◽  
Fatima F. S. Mohamed ◽  
Stephen Atkin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Serum Samples ◽  
Metabolic Markers ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Novel Biomarkers ◽  
Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

scholarly journals Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans

2018 ◽  
Vol 314 (2) ◽  
pp. E152-E164 ◽  
Author(s):  
Bryan C. Bergman ◽  
Leigh Perreault ◽  
Allison Strauss ◽  
Samantha Bacon ◽  
Anna Kerege ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Acute Exercise ◽  
Insulin Resistant ◽  
Lipid Desaturation ◽  
Intramuscular Triglyceride ◽  
Athlete’S Paradox

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the “athlete’s paradox.” We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.

scholarly journals Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer

2009 ◽  
Vol 55 (3) ◽  
pp. 425-438 ◽  
Author(s):  
Javier A Menendez ◽  
Alejandro Vazquez-Martin ◽  
Francisco Jose Ortega ◽  
Jose Manuel Fernandez-Real
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
De Novo ◽  
Genetic Alterations ◽  
Insulin Resistant

Abstract Background: An emerging paradigm supports the notion that deregulation of fatty acid synthase (FASN)-catalyzed de novo FA biogenesis could play a central role in the pathogenesis of metabolic diseases sharing the hallmark of insulin-resistance. Content: We reviewed pharmacological and genetic alterations of FASN activity that have been shown to significantly influence energy expenditure rates, fat mass, insulin sensitivity, and cancer risk. This new paradigm proposes that insulin-resistant conditions such as obesity, type 2 diabetes, and cancer arise from a common FASN-driven “lipogenic state”. An important question then is whether the development or the progression of insulin-related metabolic disorders can be prevented or reversed by the modulation of FASN status. If we accept the paradigm of FASN dysfunction as a previously unrecognized link between insulin resistance, type 2 diabetes, and cancer, the use of insulin sensitizers in parallel with forthcoming FASN inhibitors should be a valuable therapeutic approach that, in association with lifestyle interventions, would concurrently improve energy-flux status, ameliorate insulin sensitivity, and alleviate the risk of lipogenic carcinomas. Conclusions: Although the picture is currently incomplete and researchers in the field have plenty of work ahead, the latest clinical and experimental evidence that we discuss illuminates a functional and drug-modifiable link that connects FASN-driven endogenous FA biosynthesis, insulin action, and glucose homeostasis in the natural history of insulin-resistant pathologies.

scholarly journals Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

2016 ◽  
Vol 175 (5) ◽  
pp. 367-377 ◽  
Author(s):  
Christian Herder ◽  
Kristine Færch ◽  
Maren Carstensen-Kirberg ◽  
Gordon D Lowe ◽  
Rita Haapakoski ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Fasting Insulin ◽  
Subclinical Inflammation ◽  
Increased Risk

Objective Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. Design and methods We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. Results Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. Conclusions Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

scholarly journals Quantification of adipose tissue insulin sensitivity

2016 ◽  
Vol 64 (5) ◽  
pp. 989-991 ◽  
Author(s):  
Esben Søndergaard ◽  
Michael D Jensen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Healthy Humans ◽  
Metabolic Defects ◽  
Tissue Resistance

In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses.

Human aging is associated with parallel reductions in insulin and amylin release

1998 ◽  
Vol 275 (5) ◽  
pp. E785-E791 ◽  
Author(s):  
Cynthia J. Dechenes ◽  
C. Bruce Verchere ◽  
Sofianos Andrikopoulos ◽  
Steven E. Kahn
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
B Cell ◽  
Insulin Release ◽  
Cell Function ◽  
B Cell Function ◽  
Increased Risk ◽  
Older Subjects

Aging is associated with an increased risk of type 2 diabetes. To determine whether the insulin resistance of aging is associated with an increase in amylin release or whether amylin release parallels the reduction in insulin release, we studied 10 older (72 ± 2 yr) and 9 young (25 ± 1 yr) subjects. Insulin sensitivity was quantified as the insulin sensitivity index (SI) and B cell function as the acute insulin and amylin responses to iv glucose (AIRg and AARg, respectively) and iv arginine at a glucose level of >25 mM (AIRmax and AARmax). To account for the effect of SIto modulate B cell function, we calculated SI× B cell function. Older subjects were insulin resistant (SI: 4.6 ± 0.8 vs. 8.6 ± 1.4 × 10−5min−1/pM, P < 0.05). Acute responses to glucose [AIRg (older vs. young): 420 ± 106 vs. 537 ± 87 pM; AARg: 6.5 ± 1.7 vs. 9.0 ± 1.5 pM] and arginine (AIRmax: 1,096 ± 203 vs. 1,572 ± 307 pM; AARmax: 14.0 ± 3.5 vs. 16.5 ± 2.4 pM) did not differ despite the difference in SI. When adjusted for SI, insulin responses were reduced in older subjects (SI× AIRg: 1.54 ± 0.29 vs. 4.10 ± 0.63 × 10−2min−1, P = 0.001; SI× AIRmax: 4.03 ± 0.52 vs. 12.7 ± 2.9 × 10−2min−1, P < 0.01), as was amylin release (SI× AARg: 2.46 ± 0.59 vs. 6.85 ± 0.95 × 10−4min−1, P < 0.001; SI× AARmax: 4.71 ± 0.52 vs. 13.5 ± 2.2 × 10−4min−1, P < 0.001). Amylin and insulin release was proportionate, with a molar ratio of 1.5% in older and 1.4% in young subjects. Thus aging is associated with parallel impairments in the adaptation of insulin and amylin release to insulin resistance. It is unlikely that an alteration in amylin release contributes to the increased risk of type 2 diabetes.

Methods of Measuring Insulin Sensitivity

2007 ◽  
Vol 8 (4) ◽  
pp. 305-318 ◽  
Author(s):  
Kimberly K. Trout ◽  
Carol Homko ◽  
Nancy C. Tkacs
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Biological Response ◽  
Insulin Resistant ◽  
Advantages And Disadvantages ◽  
Health Disorders

Insulin resistance is a component of several health disorders, most notably impaired glucose tolerance and type 2 diabetes mellitus. Insulin-resistant individuals have an impaired biological response to the usual action of insulin; that is, they have reduced insulin sensitivity. Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method. This article describes several in vivo methods used to assess insulin sensitivity and presents the advantages and disadvantages of each.

scholarly journals The Role of GATA3 in Adipogenesis & Insulin Resistance

2020 ◽  
Author(s):  
Hend Sultan Al-Jaber ◽  
Layla Jadea Al-Mansoori ◽  
Mohamed Aghar Elrayess
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Gata3 Expression ◽  
Inflammatory State ◽  
Induced Changes ◽  
The Impact

Background: Impaired adipogenesis plays an important role in the development of obesityassociated insulin resistance and type 2 diabetes. Adipose tissue inflammation is a crucial mediator of this process. In hyperglycemia, immune system is activated partially through upregulation of GATA3, causing exacerbation of the inflammatory state associated with obesity. GATA3 also plays a role as a gatekeeper of terminal adipocyte differentiation. Here we are examining the impact of GATA3 inhibition in adipose tissue on restoring adipogenesis, reversing insulin resistance and potentially lowering the risk of type 2 diabetes. Results: GATA-3 expression was higher in insulin resistant obese individuals compared to their insulin sensitive counterparts. Targeting GATA-3 with GATA-3 specific inhibitors reversed impaired adipogenesis and induced changes in the expression of a number insulin signaling-related genes, including up-regulation of insulin sensitivity-related gene and down-regulation of insulin resistance-related genes. Conclusion: GATA3 expression is higher in differentiating adipocytes from obese insulin resistant. Inhibiting GATA3 improves adipocytes differentiation and rescues insulin sensitivity in insulin resistant cells

Abstract 040: The Effects of Coffee Consumption on Insulin Sensitivity and Other Risk Factors for Type 2 Diabetes

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Derrick Johnston Alperet ◽  
Salome Antonette Rebello ◽  
Eric Yin-Hao Khoo ◽  
Zoey Tay ◽  
Sharna Si-Ying Seah ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Controlled Trial ◽  
Coffee Consumption ◽  
Small Sample ◽  
Insulin Resistant

Background: In observational studies, coffee consumption has been consistently associated with a lower risk of type 2 diabetes mellitus. Trials examining the effect of coffee consumption on glucose metabolism have been limited by the use of surrogate insulin sensitivity indices, small sample sizes, lack of blinding, and short follow-up duration. We aimed to overcome these limitations in a randomized placebo-controlled trial examining the effects of coffee consumption on insulin sensitivity. Methodology: We conducted a 24-week randomized placebo-controlled trial in 126 overweight, insulin-resistant (HOMA-IR ≥ 1.30), Chinese, Malay and Asian-Indian males and females aged 35-69 years. Participants were randomly assigned to receive 4 cups of instant regular coffee (n=62) or 4 cups of a coffee-like placebo beverage (n=64) per day. The primary outcome was bodyweight-standardized M-value (M bw ) assessed with a hyperinsulinemic euglycemic clamp. Secondary outcomes included other clamp-based insulin sensitivity measures, biological mediators of insulin sensitivity, and measures of fasting glucose metabolism, body weight and composition. Results: Coffee consumption did not significantly change insulin sensitivity as compared with placebo [% mean difference in M bw : 0.3% (95% CI: -12.0% to 14.2%), P =0.97]. Furthermore, no significant differences in fasting plasma glucose [3.0% (-1.1% to 7.3%), P =0.16] or biological mediators of insulin resistance, such as plasma adiponectin [1.5% (-3.4% to 6.6%), P =0.55], were observed between coffee and placebo groups after 24 weeks of intervention. Coffee consumption led to a loss of body weight as compared with placebo [-1.2% (-2.3% to -0.1%), P =0.03] resulting from a decrease in fat mass [-3.7% (-7.1% to -0.2%), P =0.04] . Conclusions: Consuming 4 cups per day of caffeinated coffee for 24 weeks had no significant effect on insulin sensitivity or biological mediators of insulin resistance. Coffee consumption led to a modest decrease in body fat as compared with coffee abstinence. Trial Registration: ClinicalTrials.gov identifier: NCT01738399. Registered on 28 November 2012. Trial Sponsor: Nestlé Research Center, Lausanne, Switzerland. Trial Site: National University of Singapore.

scholarly journals FRI0052 INFLUENCE OF RHEUMATOID ARTHRITIS ON THE CLINICAL AND BIOLOGICAL PROFILE OF TYPE-2 DIABETES MELLITUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 601.2-602
Author(s):  
J. Avouac ◽  
M. Elhai ◽  
M. Forien ◽  
J. Sellam ◽  
F. Eymard ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Requirement ◽  
Multivariate Logistic Regression ◽  
Biological Profile ◽  
Research Support ◽  
Insulin Resistant ◽  
Research Grant

Background:Type-2 diabetes and rheumatoid arthritis (RA) are two chronic diseases characterized by tissue inflammation and insulin resistance. To date, no data have evaluated the influence of RA-induced joint and systemic inflammation on the course of type-2 diabetes.Objectives:To study the impact of RA on type-2 diabetesMethods:Observational, multicenter, cross-sectional usual-care study, including 7 rheumatology centers. This study included over a 24-month period consecutive patients with type-2 diabetes and RA, fulfilling the 2010 ACR / EULAR criteria, and diabetic controls with osteoarthritis (OA). The following data were collected: demographics, disease activity and severity indices, current treatment for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory (CRP levels) and metabolic (fasting glycemia and insulin levels, HbA1c) parameters. The HOMA2%B (insulin secretion) and HOMA2%S (tissue insulin sensitivity) indices (HOMA calculator, © Diabetes Trials Unit, University of Oxford) were used to assess insulin resistance. Ra and OA patients were compared using parametric tests after adjusting for age and BMI. A multivariate logistic regression was performed ti identify factors independently associated with insulin resistance.Results:We included 122 RA patients (74% women, mean age 64+/-11 years, mean disease duration 15+/-11 11 years, 75% with positive ACPA antibodies and 64% with erosive disease) and 54 controls with OA. 64% of RA patients were treated with oral corticosteroids <10 mg/day, 65% received methotrexate and 53% received targeted biological therapies.The characteristics of type-2 diabetes in the 54 OA patients corresponded to severe insulin-resistant diabetes: age> 65 years, high BMI> 30 kg/m2, mean HbA1c 7.3%+/-11 1.3%, 30% of insulin requirement, high frequency of other cardiovascular risk factors, macroangiopathy found in almost half of patients and biological criteria of insulin resistance (elevation of HOMA2%B and decrease of HOMA2%S).RA patients with type-2 diabetes had a younger age (64+/-11 years vs. 68+/-12 years, p=0.031) and lower BMI (27.7+/-11 5.5 vs. 31.5+/-11 6.3, p<0.001). These patients also had severe diabetes (HbA1c 7.0%+/-11 1.2%, 29% of insulin requirement, 43% of macroangiopathy) with an insulin resistance profile identical to OA controls. After adjusting for age and BMI, RA patients had a significantly increased insulin secretion compared to OA patients (HOMA2%B: 83.1+/-11 65.2 vs. 49.3+/-11 25.7, p=0.023) as well as a significant reduction of insulin sensitivity (HOMA2%S: 61.1+/-11 31.6 vs. 92.9+/-11 68.1, p=0.016). This insulin resistance was associated with the inflammatory activity of RA, with a negative correlation between the HOMA2%S and the DAS28 (r=-0.28, p=0.027). The multivariate logistic regression confirmed the independent association between the HOMA2%S index and DAS28 (OR: 3.93, 95% CI 1.02-15.06), as well as high blood pressure (OR: 1.29, 95% CI 0.33-1.99 CI).Conclusion:RA patients with type-2 diabetes displayed severe, poorly controlled diabetes, highlighting the burden of comorbidities associated with RA. The clinical-biological profile of diabetic RA patients was severe insulin-resistant diabetes, with a biological profile of insulin resistance linked to the inflammatory activity of the disease. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.Acknowledgments:Société Française de Rhumatologie (research grant)Bristol Myers Squibb (research grant)Disclosure of Interests:Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Muriel ELHAI: None declared, Marine Forien: None declared, Jérémie SELLAM: None declared, Florent Eymard Consultant of: Regenlab, Anna Moltó Grant/research support from: Pfizer, UCB, Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, UCB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Frédéric Banal: None declared, Joel Daminano: None declared, Philippe Dieudé: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

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